Luteolin inhibits melanoma growth in vitro and in vivo via regulating ECM and oncogenic pathways but not ROS
Luteolin inhibits melanoma growth in vitro and in vivo via regulating ECM and oncogenic pathways but not ROS
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木犀草素通过调节 ECM 和致癌途径而非 ROS 抑制体外和体内黑色素瘤生长
DOI：
10.1016/j.bcp.2020.114025
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发表时间：
2020-07-01
影响因子：
5.8
通讯作者：
Liu-Smith, Feng
中科院分区：
文献类型：
--
作者：
Schomberg, John;Wang, Zi;Liu-Smith, Feng
在之前的研究中，木犀草素在体外抑制了多种癌细胞的生长，但体内研究有限，并且对基因组水平的分子机制没有全面的了解。本研究确定毛地黄黄酮作为一种有效的药物，抑制黑色素瘤细胞生长在体外和体内。分子研究和基因组分析用于确定毛地黄黄酮在黑色素瘤细胞中的作用机制。作为ROS（活性氧）清除剂，毛地黄黄酮出乎意料地诱导ROS;但是与抗氧化剂NAC或mito-TEMPO共处理不能挽救细胞生长抑制，尽管ROS水平降低。接下来，我们使用RNA-Seq分析了4种黑色素瘤细胞系中木犀草素诱导的差异表达基因（DEG），并使用生物信息学软件（包括PharmetRx）的组合进行了途径分析，该软件在发现潜在药物的药理学途径方面特别有效。我们的研究结果表明，毛地黄黄酮诱导三个主要方面的变化：细胞-细胞相互作用途径（细胞外基质，ECM），致癌途径和免疫应答信号通路。基于这些结果，我们进一步验证了当细胞以低密度接种时，木犀草素在抑制细胞增殖方面特别有效，同时伴有纤连蛋白积累的下调。总之，通过在总共4种黑色素瘤细胞系中进行广泛的DEG分析，我们发现木犀草素介导的黑色素瘤细胞生长抑制可能不是通过ROS诱导，而是可能通过同时作用于多个途径，包括ECM（细胞外基质）途径、致癌信号传导和免疫应答途径。有必要对这种有前途的化合物的机制进行进一步研究，并且可能会应用于癌症患者，因为其安全药理学已在自闭症患者中得到验证。
Luteolin inhibited growth of several cancer cells in vitro in previous studies, with limited in vivo studies, and no comprehensive understanding of molecular mechanisms at genomics level. This study identified luteolin as an effective agent to inhibit melanoma cell growth in vitro and in vivo. Molecular studies and genomic profiling were used to identify the mechanism of action of luteolin in melanoma cells. As a ROS (reactive oxygen species) scavenger, luteolin unexpectedly induced ROS; but co-treatment with antioxidants NAC or mito-TEMPO did not rescue cell growth inhibition, although the levels of ROS levels were reduced. Next, we profiled luteolin-induced differentially expressed genes (DEGs) in 4 melanoma cell lines using RNA-Seq, and performed pathway analysis using a combination of bioinformatics software including PharmetRx which was especially effective in discovering pharmacological pathways for potential drugs. Our results show that luteolin induces changes in three main aspects: the cell-cell interacting pathway (extracellular matrix, ECM), the oncogenic pathway and the immune response signaling pathway. Based on these results, we further validated that luteolin was especially effective in inhibiting cell proliferation when cells were seeded at low density, concomitantly with down-regulation of fibronectin accumulation. In conclusion, through extensive DEG profiling in a total of 4 melanoma cell lines, we found that luteolin-mediated growth inhibition in melanoma cells was perhaps not through ROS induction, but likely through simultaneously acting on multiple pathways including the ECM (extracellular matrix) pathway, the oncogenic signaling and the immune response pathways. Further investigations on the mechanisms of this promising compound are warranted and likely result in application to cancer patients as its safety pharmacology has been validated in autism patients.